Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

• 批准号: 9121477
• 负责人: Jorge E Galan
• 金额: $ 50.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121477
• 关键词: Accounting; Animal Model; Applications Grants; Bacteria; Binding; Biology; Cells; Cessation of life; Data; Deoxyribonucleases; Developing Countries; Development; Disease; Disease Outbreaks; Exhibits; Food Poisoning; Foundations; Gastroenteritis; Genome; Growth; Health; Homologous Gene; Human; Infection; Knowledge; Laboratories; Lead; Life; Link; Location; Molecular; Mus; Neuraminic Acids; Pathogenesis; Pathway interactions; Pertussis; Pertussis Toxin; Polysaccharides; Prevention; Prevention strategy; Production; Publishing; Recording of previous events; Research; Role; Salmonella; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Series; Site; Specificity; Structure; Surface; Symptoms; Therapeutic; Toxin; Transferase; Typhoid Fever; United States; Vaccines; Vacuole; Vertebrates; Vesicle; Virulence; Virulence Factors; Work; autocrine; base; combat; cytolethal distending toxin; extracellular; genetic information; genome sequencing; insight; mouse model; novel; novel therapeutics; paracrine; pathogen; receptor

DESCRIPTION (provided by applicant): Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~500,000 deaths every year. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause limited gastroenteritis (e. g. food poisoning), S. Typhi and S. Paratyphi are exclusive human pathogen and causes systemic, often lethal, disease. Despite being one of the earliest recognized pathogens in human history, the pathogenesis of S. Typhi still remains poorly understood. The molecular bases for S. Typhi's remarkable host specificity are also poorly understood. Genome sequence data suggest that a combination of genome degradation and acquisition of unique genetic information may account for S. Typhi's unique biology. One of the very few virulence factors that are unique to typhoidal serovars of S. enterica is Typhoid toxin, which was recently discovered in our laboratory. Typhoid toxin is an atypical AB toxin in that it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) and a deoxyribonuclease (CdtB), which are homologs of the active subunits of pertussis and cytolethal distending toxins, respectively. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. We have recently discovered that systemic administration of purified typhoid toxin can recapitulate many of the symptoms of typhoid fever in mice. This is a very exciting discovery since it not only links typhoid toxin to the pathogenesis of typhoid fever but also provides concrete bases for the development of novel prevention as well as potentially life-saving therapeutic strategies. Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellularly located bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole. From this location, the toxin is then packaged into vesicle carriers and exported to the extracellular medium, from where it finds its way into target cells by interacting with specific surface receptors. Our laboratory has recently identified the surface receptors for typhoid toxin, which revealed unique insights into the biology of this toxin. In addition, we have discovered that a Rab32 and BLOC-3-dependent pathogen surveillance mechanism restricts the growth of S. Typhi in mice. We intend to leverage these exciting findings to carry out a series of research objectives that, through the study of typhoid toxin, we hope will deepen our understanding of typhoid fever and the pathogenesis of S. Typhi infection.

描述（由申请人提供）：肠道沙门氏菌血清型伤寒（S. Typhi）和相关的血清型副伤寒沙门氏菌引起人类伤寒，这是一种破坏性疾病，每年导致约500,000人死亡。虽然大多数病例发生在发展中国家，但美国偶尔也会爆发疫情。与其他可感染多种宿主并可引起有限肠胃炎（如食物中毒）的肠沙门氏菌血清型不同，伤寒沙门氏菌和副伤寒沙门氏菌是人类独有的病原体，可引起全身性、往往致命的疾病。尽管是人类历史上最早发现的病原体之一，但对伤寒沙门氏菌的发病机制仍然知之甚少。伤寒沙门氏菌显著的宿主特异性的分子基础也知之甚少。基因组序列数据表明，基因组降解和获得独特遗传信息的结合可能解释了伤寒沙门氏菌独特的生物学特性。伤寒毒素是肠链球菌伤寒血清型所特有的极少数毒力因子之一，这是最近在我们实验室发现的。伤寒毒素是一种非典型AB毒素，因为它有两个酶活性亚基：ADP核糖基转移酶（PltA）和脱氧核糖核酸酶（CdtB），它们分别是百日咳和细胞毒性膨胀毒素的活性亚基的同源物。这两个亚基彼此共价连接，并与由PltB组成的同戊美亚基B相关联。我们最近发现，系统管理纯化伤寒毒素可以重现伤寒的许多症状在小鼠。这是一个非常令人兴奋的发现，因为它不仅将伤寒毒素与伤寒的发病机制联系起来，而且为开发新的预防和潜在的挽救生命的治疗策略提供了具体的基础。伤寒毒素表现出非凡的生物学特性，它仅由位于细胞内的细菌产生，并在其合成和组装后释放到含有沙门氏菌的液泡中。从这个位置，毒素被包装成囊泡载体，并出口到细胞外培养基，从那里它找到进入靶细胞的途径